ABSTRACT Sickle cell disease (SCD) is the commonest genetic disorder in the World. It is most prevalent in Africa. Penicillin prophylaxis in neonates identified by newborn screening has reduced mortality in SCD. However, this progress has not been matched by advancements in reducing deaths due to other causes. End-stage organ damage is now the leading cause of death among SCD patients in the West and it is poised to become the major cause of death in Africa once prevention and prompt management of infections becomes widely implemented on the continent. Inflammatory molecules such as heme released from hemolysis cause severe tissue injury that ultimately causes organ damage in SCD. Hemolysis raises circulating levels of free heme and cell-free hemoglobin sufficiently to cause tissue injury. Our prior studies reported in the Journal of Clinical Investigations showed that a modest elevation of circulating heme that has no impact on transgenic sickle cell trait mice causes a lethal damage to the lungs in littermates with SCD in a condition commonly called acute chest syndrome (ACS). Our preliminary studies show that excess circulating heme can also cause acute kidney injury (AKI) in transgenic sickle cell mice. Together these findings highlight proteins that can neutralize heme as potential alleviators of the organ damage seen in SCD patients who develop hyper- hemolysis. In support of this idea, we reported previously that a (GT)n dinucleotide polymorphism associated with increased activity of heme oxygenase-1 (HO-1), the rate limiting heme degradation enzyme is linked to significantly lower rates of ACS. There are four other key hemolysis cytoprotective proteins (HCPs); hemopexin, alpha-1 microglobulin, ferritin and haptoglobin. We reason that these HCPs are modifiers of acute organ damage in SCD. Remarkably, there has not previously been a genome-wide association study (GWAS) to identity the genetic factors that influence the level of the three HCPs that directly detoxify heme; HO-1, hemopexin and alpha-1 microglobin. Suggestive of a variable cyto-protective defense among SCD patients, our preliminary studies show a wide range of levels (up to 300-fold variation) for each of the five key HCPs in a cohort of SCD patients in Ghana. We will perform a GWAS to identify variants associated with the level of the five HCPs in two large cohorts SCD patients in Ghana, and replicate our findings in three large patient cohorts in Cameroon, Nigeria and Tanzania. This geographical coverage will ensure that we capture the genetics of variable HCP expression among SCD patients across the African continent. We will then longitudinally follow these cohorts to determine whether variants associated with raised HCP level protect patients from acute organ damage during vaso-occlusive crisis and hyper hemolysis. This project will provide a unique opportunity for African scientists to study genomics of SCD, including experiments using transgenic SCD mice for the first time on the continent, to help fulfill the central objective of the H3Africa consortium.